PROJECT SUMMARY/ABSTRACT Natural products from bacteria have long been the frontline defense in the struggle against bacterial infections, and have also found wide use as antifungals, anthelminthics, anti-cancer drugs, and immunosupressants. One group of bacteria, the actinomycetes, has historically been the deepest source of clinically-useful natural products. Recent work has demonstrated that natural product biosynthesis often results from microbial communication in the form of interactions between cells in colonies of a single actinomycete, or by interactions with microbes of different species. Together, these observations underscore the idea that induction of natural product biosynthesis is socially-driven. The goal of this study is to understand how inter- and intra- species interactions activate natural product biosynthesis at a molecular level. Our first research objective seeks a mechanistic understanding of how a model actinomycete, Streptomyces coelicolor, activates expression of genes for natural product biosynthesis in the presence of other actinomycetes. We have found that this activation requires an unusual and poorly-understood signal transduction mechanism found in actinomycetes that shares parallels with eukaryotic systems that rely on G protein activation. Our second research objective seeks a systems-level understanding of natural product biosynthesis in S. coelicolor within the context of cell fate decisions. Knowledge generated from this objective may be employed to someday manipulate cell fates within actinomycete cultures to drive natural products discovery and production. These objectives run in parallel with our efforts to build a microfluidic device for studying microbial interspecies interactions with unprecedented speed, throughput, and specificity. This device will have multiple applications related to our first two objectives and beyond. This research will illuminate the social aspect of natural product biosynthesis, and in the long term, provide a foundation for harnessing microbial social cues and genetic regulation to maximize future natural products discovery efforts. !